The bacterial signaling molecule cyclic diguanosine monophosphate (c-di-GMP) is responsible for regulating bacterial responses to a variety of environmental factors, including aggregation into the biofilm state (Hengge, R., Nat. Rev. Microbiol. 2009, 7, 263-273; Krasteva, P. V., et al., Protein Sci. 2012, 21, 929-948; Mills, E.; et al., Cell. Microbiol. 2011, 13, 1122-1129; Povolotsky, T. L.; et al., J. Biotechnol. 2012, 160, 10-16; Quin, M. B.; et al., J., Structure 2012, 20, 350-363; Sondermann, H.; et al., Curr. Opin. Microbiol. 2012, 15, 140-146). Binding of c-di-GMP as a monomer and as a self-intercalated dimer to the PilZ domain proteins has been demonstrated (Hengge, R., Nat. Rev. Microbiol. 2009, 7, 263-273; Krasteva, P. V., et al., Protein Sci. 2012, 21, 929-948; Schirmer, T.; et al., Nat Rev Micro 2009, 7, 724-735; Ko, J.; et al., J. Mol. Biol. 2010, 398, 97-110). Activation of two different classes of riboswitches in noncoding regulatory mRNA domains has also been identified upon binding c-di-GMP (Shanahan, C. A.; et al., J. Am. Chem. Soc. 2011, 134, 15578-15592; Smith, K. D.; et al., Nat. Struct. Mol. Biol. 2009, 16, 1218-1223; Smith, K. D.; Shanahan, C. A.; et al., Proc. Natl. Acad. Sci. USA 2011, 108, 7757-7762; Sudarsan, N.; et al., Science (Wash.) 2008, 321, 411-413). Finally, c-di-GMP, among other cyclic dinucleotides, plays a role in triggering an innate immune response (Karaolis, D. K. R.; et al., J. Immunol. 2007, 178, 2171-2181; Woodward, J. J.; et al., Science 2010, 328, 1703-1705) through a transmembrane protein named STING in the innate immune sensing pathway, where a specific receptor for cyclic dinucleotides has been identified (Burdette, D. L.; et al., Nature 2011, 478, 515-518).
Currently there is a need for agents that are useful for activating the innate immune system. Such activation may be beneficial for treating certain diseases or conditions. There is also a need for agents that are useful for treating bacterial infections, viral infections and/or cancer.